Methods Of Treating Pruritus

ABSTRACT

The present disclosure related to methods of treating pruritus in a subject by topically administering detomidine, or a pharmaceutically acceptable salt thereof, to the subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/864,400, filed May 1, 2020, which claims the benefit of U.S.Provisional Application Nos. 62/841,373, filed May 1, 2019, 62/862,481,filed Jun. 17, 2019, and 62/960,027, filed Jan. 12, 2020, the entiretiesof which are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure related to methods of treating pruritus in asubject by topically administering detomidine, or a pharmaceuticallyacceptable salt thereof, to the subject.

BACKGROUND

Pruritus is an unpleasant sensation that provokes the desire to scratch.The condition is extremely common with estimates that at any given timebetween 8 and 16% of adults are suffering from it, resulting insignificant reductions in quality of life for sufferers. To date,despite numerous attempts at clinical studies, no drug has been approvedto treat the condition.

Detomidine is a synthetic alpha-2 adrenoreceptor agonist with sedativeand analgesic properties. It is presently sold by prescription under thetrade name DORMOSEDAN® (Zoetis Services LLC, Parsippany, N.J.) as asedative and anesthetic premedication in connection with a variety ofminor surgical and diagnostic procedures on horses and other largeanimals. It is commonly combined with butorphanol in order to increasethe degree of analgesia and depth of sedation, and may also be used withketamine for intravenous anesthesia of short duration. The route ofadministration of DORMOSEDAN® injection is typically intramuscular orintravenous, but the drug is also available as a gel (DORMOSEDAN GEL®)that may be administered by the sublingual route. More recently,detomidine has been shown to be effective as a topical analgesic agent.

SUMMARY OF THE INVENTION

The present invention relates to the topical treatment of pruritus bydetomidine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: A graphical representation of mechanical sensitivity over time.

FIG. 2: Images of immunostaining of pig skin biopsies at ×200 (a) and×400 (b, c) magnification.

FIG. 3: A graphical representation of scratching events over time.

DETAILED DESCRIPTION

The present inventions may be understood more readily by reference tothe following detailed description taken in connection with anyaccompanying figures and examples, which form a part of this disclosure.It is to be understood that these inventions are not limited to thespecific products, methods, conditions or parameters described and/orshown herein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed inventions.

The entire disclosures of each patent, patent application, andpublication cited or described in this document are hereby incorporatedherein by reference.

As employed above and throughout the disclosure, the following terms andabbreviations, unless otherwise indicated, shall be understood to havethe following meanings.

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “aparticle” is a reference to one or more of such particles andequivalents thereof known to those skilled in the art, and so forth.Furthermore, when indicating that a certain element “may be” X, Y, or Z,it is not intended by such usage to exclude in all instances otherchoices for the element.

When values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. As used herein, “about X” (where X is a numerical value)preferably refers to ±10% of the recited value, inclusive. For example,the phrase “about 8” preferably refers to a value of 7.2 to 8.8,inclusive; as another example, the phrase “about 8%” preferably refersto a value of 7.2% to 8.8%, inclusive. Where present, all ranges areinclusive and combinable. For example, when a range of “1 to 5” isrecited, the recited range should be construed as optionally includingranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like.In addition, when a list of alternatives is positively provided, such alisting can also include embodiments where any of the alternatives maybe excluded. For example, when a range of “1 to 5” is described, such adescription can support situations whereby any of 1, 2, 3, 4, or 5 areexcluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not2”, or simply “wherein 2 is not included.” The phrase “at least about x”is intended to embrace both “about x” and “at least x”. It is alsounderstood that where a parameter range is provided, all integers withinthat range, and tenths thereof, are also provided by the invention. Forexample, “2-5 hours” includes 2 hours, 2.1 hours, 2.2 hours, 2.3 hoursetc. . . . up to 5 hours.

“Subject,” as used herein, includes humans and animals. The terms“human,” “patient,” and “subject” are used interchangeably herein.

The present invention relates to methods of treating pruritus in asubject comprising topically administering to the subject's skin,detomidine or a pharmaceutical composition comprising detomidine.According to the invention, the amount of detomidine topicallyadministered to the subject is sufficient to treat pruritus. Prurituscan be demonstrated to have been treated by reductions in VAS, NRS,Quality of Life and/or pruritus scores or by other methods known in theart.

The detomidine may be topically administered as the free base form or asa salt. Unless specified otherwise, reference to “detomidine” in thepresent disclosure can refer to detomidine in a free base form, or to asalt of detomidine. Those of ordinary skill in the art can readilyidentify exemplary pharmaceutically acceptable salt forms of detomidine.Suitable pharmaceutically acceptable salts of detomidine includedetomidine bitartrate, detomidine bitartrate hydrate, detomidinehydrochloride, detomidine p-toluenesulfonate, detomidine phosphate,detomidine thiosemicarbazone, detomidine sulfate, detomidinetrifluoroacetate, detomidine hemipentahydrate, detomidine bitartratehemipentahydrate, detomidine pentafluoropropionate, detomidinep-nitrophenylhydrazone, detomidine o-methyloxime, detomidinesemicarbazone, detomidine hydrobromide, detomidine mucate, detomidineoleate, detomidine phosphate dibasic, detomidine phosphate monobasic,detomidine inorganic salt, detomidine organic salt, detomidine acetatetrihydrate, detomidine bis(heptafluorobutyrate), detomidinebis(methylcarbamate), detomidine bis(pentafluoropropionate), detomidinebis(pyridine carboxylate), detomidine bis(trifluoroacetate), detomidinechlorhydrate, and detomidine sulfate pentahydrate. In certainembodiments of the presently disclosed dosage forms, the detomidine ispresent as the hydrochloride salt. In certain embodiments, thedetomidine is anhydrous detomidine hydrochloride. In other embodiments,the detomidine is detomidine hydrochloride monohydrate.

In some embodiments, the pruritus is acute. Acute pruritus is thedefined as the manifestation of the condition for up to six consecutiveweeks. In other embodiments, the pruritus is chronic. Chronic pruritusis defined as the manifestation of the condition for more than sixconsecutive weeks.

In certain embodiments, the origin of the pruritus is unknown. In otherembodiments, the pruritus comprises the symptom of a dermatological,neurological, psychogenic or systemic condition, or is of mixed origin.

Examples of pruritic dermatological conditions include atopicdermatitis, contact dermatitis, allergic dermatitis, seborrheicdermatitis, statis dermatitis, pityriasis rubra pilaris, pityriasisrosea, acne, dermatitis herpetiformis, pemphigus vulgaris, bullouspemphigoid, lichen planus, prurigo nodularis, lichen simplex chronicus,lichen amyloidosis, urticaria, mastocytosis, polymorphous lighteruption, actinic prurigo, chronic prurigo, actinic dermatitis,polymorphic eruption of pregnancy, eosinophilic folliculitis,dermatomyositis, prurigo pigmentosa, lichen sclerosus, palmoplantarpustulosis, pompholyx, idiopathic xerosis, scarring, burns, burn scars,keloid scars, hypertrophic scars, reactive drug eruptions and pruritusof an infestive or infective origin.

Examples of pruritic infestive conditions include scabies, pediculosisand arthropod bites.

Examples of pruritic infective conditions include fungal, parasitic,viral and bacterial conditions.

Examples of pruritic neurological conditions include notalgiaparesthetica, brachioradial pruritus, postherpetic neuralgia, stroke,small fiber neuropathy, trigeminal trophic syndrome, Creutzfeldt-Jakobdisease, chemotherapy-induced neuropathy, HIV-related neuropathy andmultiple sclerosis.

Examples of pruritic psychogenic conditions include depression, anxiety,psychogenic excoriation, anorexia nervosa and delusional parasitosis.

Examples of pruritic systemic conditions include chronic renal failure,uremic pruritus, liver disease, primary biliary cholangitis, primarybiliary cirrhosis, cholestatic jaundice, hepatitis C, cholestasis ofpregnancy, polycythemia vera, iron deficiency anemia, Hodgkin lymphoma,non-Hodgkin lymphoma, multiple myeloma, hematologic orlymphoproliferative disorders, primary cutaneous lymphoma, mycosisfungoides, cutaneous T cell lymphoma, malignancy, plasma celldyscrasias, gastric carcinoid tumors, hyperthyroidism, hypothyroidism,hyperparathyroidism, haemochromatosis, celiac disease, systemic lupuserythematosus, systemic sclerosis, diabetes, carcinoid syndrome,dermatomyositis, scleroderma, Sjögren's syndrome, linear immunoglobulinA (IgA) disease, graft-versus-host disease, Darier disease,Hailey-Hailey disease, porphyria and amyloidosis.

Pruritus is understood to occur when pruritogens activate receptors onsmall itch-selective unmyelinated C-fibers. Two subtypes ofitch-sensitive neurons are found in the dermal tissues, histaminergicand non-histaminergic neurons, each with different tracts and differentpatterns of brain activation.

Histaminergic neurons are primarily involved in acute pruritus.Histamine is released by mast cells and other immune cells andkeratinocytes. H1 and H4 receptors on histaminergic nerves bindhistamine and activate TRPV1 through the phospholipase system. Theexcited histaminergic neurons also release neuropeptides such ascalcitonin gene-related protein and substance P, which can causeinflammatory effects such as local vasodilation, plasma extravasation,and mast cell degranulation.

Non-histaminergic neurons can be excited by endogenous/exogeneouspruritogens other than histamine and express various receptors involvedin pruritus. These receptors activate either TRPV1 or TRPA1 through thephospholipase or kinase system.

As shown in WO2018129313, which is incorporated herein in its entirety,detomidine has been demonstrated to be effective as a topical agent forthe treatment of pain. Without wanting to be bound to any particulartheory, it is believed that when administered topically, detomidine caninhibit peripheral pruritus signal transduction in a similar manner toits inhibition of peripheral pain signal transduction. Furthermore, inaddition to its well established use as an alpha-2 adrenoreceptoragonist, surprisingly, it has now been found that detomidine possesses avariety of additional receptor binding properties which are believed tocontribute to its ability to topically treat pruritus.

In certain embodiments, the detomidine is administered topically inpharmaceutical compositions comprising about 0.01 to about 5 wt % ofdetomidine. For example, the pharmaceutical compositions comprise about0.01, 0.02, 0.03, 0.033, 0.04, 0.05, 0.06, 0.066, 0.07, 0.08, 0.09, 0.1,0.2, 0.3, 0.33, 0.4, 0.5, 0.6, 0.66, 0.7, 0.8, 0.9, 1, 1.33, 1.5, 1.66,2, 2.33, 2.5, 2.66, 3, 3.33, 3.5, 3.66, 4, 4.33, 4.5, 4.66 or 5 wt % ofdetomidine. In certain embodiments, the pharmaceutical compositionscomprise 0.033, 0.1, 0.33 or 1 wt % of detomidine. In a preferredembodiment, the pharmaceutical composition comprises 0.1 wt % ofdetomidine. In another preferred embodiment, the pharmaceuticalcomposition comprises 0.33 wt % of detomidine. In another preferredembodiment, the pharmaceutical composition comprises 1 wt % ofdetomidine.

In certain embodiments, the topically administered detomidine is theonly, or sole, active agent being administered to treat pruritus. Inother embodiments, the topically administered detomidine is administeredin combination with at least one additional active agent. In certainembodiments, the additional active agent is also administered topically,either in a combined, or as separate, pharmaceutical compositions. Inother embodiments, the additional active agent is administered orally orparenterally. Examples of parenteral administration include intravenous,intramuscular, subcutaneous, rectal, sublingual, buccal, inhaled andintrathecal administrations.

Examples of additional active agents include corticosteroids, doxepine,tacrolimus, pimecrolimus, pramoxine, lidocaine, prilocaine, ketamine,amitriptyline, capsaicin, menthol, camphor, strontium, tofacitinib,crisaborole, N-palmitoylethanolamine, antihistamines, SNRIs, SSRIs,naltrexone, butophanol, nalfurafine, gabapentin, pregabalin, aprepitant,thalidomide, lenalidomide, ursodeoxycholic acid, rifampin,cholestyramine, phenobarbital, Botulinum toxin A, naloxone, ASN008,SNA-125, TS-022, KPL-716 and orvepitant.

Examples of corticosteroids include alclometasone, amcinonide,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,clobetasone, clocortolone, cortisone, desonide, desoximetasone,dexamethasone, diflorasone, fluocinolone, fluocortolone, fluprednidene,flurandrenolide, fluticasone, halcinonide, halobetasol, halometasone,hydrocortisone, mometasone, methylprednisolone, prednicarbate,prednisolone, prednisone, tixocortol, triamcinolone and mometasone.

Examples of anti-histamines include acrivastine, azelastine, bilastine,bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine,cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine,cyclizine, cyproheptadine, desloratadine, dexbrompheniramine,dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine,doxylamine, ebastine, embramine, fexofenadine, hydroxyzine,levocabastine, levocetirizine, loratadine, meclizine, mirtazapine,olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, rupatadine, tripelennamine and triprolidine.

Examples of SNRIs include venlafaxine, duloxetine, milnacipran,mirtazapine and levomilnacipran.

Examples of SSRIs include fluoxetine, fluvoxamine, paroxetine,sertraline, citalopram and escitalopram.

In certain embodiments, the detomidine is topically administered oncedaily to treat pruritus. In other embodiments, the detomidine istopically administered twice daily to treat pruritus. In otherembodiments, the detomidine is topically administered three times dailyto treat pruritus.

Detomidine is administered topically to treat pruritus in the form of apharmaceutical composition. Examples of pharmaceutical compositions forthe topical administration of detomidine to treat pruritus include gels,creams, ointments, emulsions, emu-gels, foams, suspensions andspray-patches. In a preferred embodiment, the detomidine is topicallyadministered in the form of a gel.

In one embodiment, the present invention relates to a method of treatingpruritus comprising the topical administration of a 0.033 wt % gel ofdetomidine. In another embodiment, the present invention relates to amethod of treating pruritus comprising the topical administration of a0.1 wt % gel of detomidine. In another embodiment, the present inventionrelates to a method of treating pruritus comprising the topicaladministration of a 0.33 wt % gel of detomidine. In another embodiment,the present invention relates to a method of treating prurituscomprising the topical administration of a 1 wt % gel of detomidine. Inone embodiment, the administration is once daily. In another embodiment,the administration is twice daily.

Topical administration of the pharmaceutical compositions to a subjectcan result in a blood plasma concentration in the subject that is lessthan that required to achieve a systemic therapeutic effect of thedetomidine. Preferably, the topical administration can continue forweeks, months, or longer while maintaining a sub-therapeutic systemicblood plasma concentration and with minimal or no medically relevanteffect outside of that bodily region, or simply minimal or no medicallyrelevant systemic effect.

In certain embodiments, the pharmaceutical compositions of the presentinvention provide prolonged, substantially non-systemic treatment forpruritus. The period of time over which the pharmaceutical compositionscan provide treatment for pruritus is up to 24 hours when topicallyapplied once a day. In certain embodiments, the pharmaceuticalcompositions are preferably applied twice per day, and in such instancesthe treatment of pruritus that is provided by a first of the two topicaladministrations has a duration that lasts until the second topicaladministration, and the second daily topical administration has aduration that lasts until the following day's first topicaladministration. As used herein, “substantially non-systemic” refers to atreatment effect that is localized to the bodily region (for example,body part) to which the pharmaceutical compositions is topicallyapplied, with a minimal or no medically relevant effect outside of thatbodily region, or simply no minimal or no medically relevant systemiceffect.

Examples of gels, creams, ointments, emulsions, emu-gels, foams,suspensions and spray-patches of detomidine are described inWO2018129313 and WO2020012415, each of which are incorporated herein byreference in their entireties.

The pharmaceutical compositions of detomidine for topical administrationcan also include a carrier that is suitable for topical administrationto a subject's skin. The carrier may include, for example, asolubilizer, a buffer, or both. The carrier can also be a mixture of ahydrophilic phase member and a hydrophobic phase member. As describedbelow, the formulation may also include one or more additionalcomponents in order to produce the topical form, such as thickening orgelling agents, preservatives, antioxidants, permeation enhancers,emulsifying agents, emollients, or humectants.

Examples of solubilizers include alcohols, such as sugar alcohols,diols, polyols, or polyether alcohols, fatty acids, organic solvents,waxes, oils, poloxamers, cyclodextrins, or any combination thereof. Forexample, the solubilizer may be glycerol, polyethylene glycol (such asPEG 3350), propylene glycol, poloxamer 124, poloxamer 407, Labrasol®(caprylocaproyl polyoxyl-8 glycerides), Kleptose® HPB, Captisol®sulfobutylether β-cyclodextrin, or any combination thereof. In someembodiments, the solubilizer is glycerol, propylene glycol, polyethyleneglycol, or any combination thereof. For example, the water-misciblesolubilizer may include both glycerol and propylene glycol.

Examples of hydrophilic phase members include water, glycerol,polypropylene glycol, polyethylene glycol, ethanol, benzyl alcohol,1,3-propanediol, 1,2-pentanediol, propylene carbonate,2-(2-ethoxyethoxy)ethanol, dimethyl isosorbide, tetraglycol,pyrrolidone, dimethylacetamide, caprylocaproyl polyoxyl-8 glycerides,hexylene glycol, butylene glycol, or any combination thereof. Thehydrophilic phase member may also comprise an aqueous buffer solution.For example, the hydrophilic phase member may comprise 0.01 to 1.0Mcitrate, phosphate, Tris, carbonate, succinate, tartrate, borate,imidazole, maleate, or phthalate buffer at pH 4.5-9.0.

Examples of hydrophobic phase members include aromatic hydrocarbons,alkane, cycloalkanes, alkynes, terpenes, organic oils, mineral oils, orany combination thereof. Exemplary hydrophilic phase members includemineral oil, isopropyl isostearate, isostearyl isostearate, alkylbenzoate, butyl stearate, diisopropyl adipate, diethylhexyl adipate,caprilic/capric triglyceride, isocetyl stearate, isopropyl myristate,isopropyl palmitate, lauryl lactate, myristil myristate, ethylhexylcocoate, ethylhexyl palmiatate, ethylhexyl pelagronate, ethylhexylstearate, diethylhexyl succinate, propylene glycoldicaprylate/dicaprate, PPG-2 myristyl ether propionate, pentaerythrityltetracaprylate/caprate, pentaerythrityl tetraisostearate, PEG 2 stearylether, steareth-21, and isotridecyl isononanoate. An exemplary genus ofhydrophobic phase members is medium chain triglycerides. Furtherhydrophobic phase members that represent fatty acid esters are disclosedin U.S. Pub. No. 2012/0201863, the entire contents of which areincorporated herein by reference.

Examples of thickening or gelling agents can include hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, xanthan gum, carbomers (acrylates andacrylic acid and its derivatives polymers, such as Carbopol® 980(crosslinked polyacrylate polymer)), povidones (e.g.,polyvinylpyrrolidone), Poloxamers, Polyamide-3 (e.g., OleoCraft™ HP33),and other appropriate agents.

Examples of preservatives can include benzalkonium chloride, parabens,sorbic acid and its salts, benzoic acid and its salts, cetrimoniumbromide and chloride salts, phenoxyethanol, and other agents.

Examples of antioxidants can include sodium metabisulfite, ascorbicacid, tocopheryl acetate (for purely aqueous formulations), and BHT orBHA (for hydrophobic formulations).

Examples of permeation enhancers can include Transcutol® P (highlypurified diethylene glycol monoethyl ether EP/NF) or dimethylisosorbide(DMI).

Examples of emulsifying agents can include Tweens, Spans, poloxamers(124, 407, 188), Brij S2 and Brij 721, Crodex M (cetearyl alcohol andpotassium cetyl Phosphate), Crodafos CES (cetearyl alcohol and dicetylphosphate and Ceteth-10 phosphate (Crodafos CES), Cithrol DPHS (PEG 30Dipolyhydroxystearate), cyclopentasiloxane, or macrogol hydroxystearate.

Examples of emollients can include, but are not limited to, Migliol 810or 812 (caprylic-capric triglycerides), Isoporpyl Isostearate (CrodamolIPIS), Isostearyl Isostearate (Crodamol ISIS), PPG-11 Stearyl Ether(Arlamol PS HE), Macrogol 6 Glycerol Caprylocaprate (Glycerox 767HC), orLabrasol® (caprylocaproyl polyoxyl-8 glycerides).

Examples of humectants can include, but are not limited to, glycerin,propylene glycol, 1,3-propanediol, or 1,2-pentanediol.

In certain embodiments, the topical pharmaceutical compositions comprise0.01 to 5 wt % detomidine hydrochloride, glycerine, propylene glycol, agelling agent, and a buffer that is effective to maintain thepharmaceutical composition at pH about 4.5 to about 8.2. In someembodiments, the topical pharmaceutical compositions comprise 0.01 to 3wt % detomidine hydrochloride, glycerine, propylene glycol, a cellulosegelling agent, and a buffer that is effective to maintain thepharmaceutical composition at pH about 4.5 to about 6. In some otherembodiments, the topical pharmaceutical compositions comprise 0.05 to 3wt % detomidine hydrochloride, glycerine, propylene glycol, a cellulosegelling agent, and a buffer that is effective to maintain thepharmaceutical composition at pH about 5 to about 6. In yet otherembodiments, the topical pharmaceutical compositions comprise 0.1 to 2wt % detomidine hydrochloride, glycerine, propylene glycol, a cellulosegelling agent, and a buffer that is effective to maintain thepharmaceutical composition at pH about 5 to about 5.5. In still otherembodiments, the topical pharmaceutical compositions comprise 0.1 to 1wt % detomidine hydrochloride, glycerine, propylene glycol, hydroxyethyl cellulose, and a buffer that is effective to maintain thepharmaceutical composition at pH about 5 to about 5.5. In yet otherembodiments, the topical pharmaceutical compositions comprise 0.1 to 1wt % detomidine hydrochloride, glycerine, propylene glycol, hydroxyethyl cellulose, and a buffer that is effective to maintain thepharmaceutical composition at pH about 5.2 to about 5.5. Any of theseembodiments may further comprise a preservative.

In certain embodiments, the topical pharmaceutical compositions compriseat least about 0.01 weight percent of detomidine, based on the totalweight of the composition. In some embodiments, detomidine is present inan amount in the range of about 0.01 to about 0.5 weight percent. Insome other embodiments, detomidine is present in an amount in the rangeof about 0.01 to about 0.25 weight percent. In yet another embodiment,detomidine is present in an amount in the range of about 0.01 to about0.075 weight percent. As discussed herein, all weight percentage ofdetomidine is calculated based on the weight of the topicalpharmaceutical composition, e.g., a gel.

The pharmaceutical compositions may include a volatile solvent that atleast partially evaporates from the skin surface following application.For example, in certain embodiments, the buffer component is aqueous,and the water that is contained within the aqueous buffer represents thevolatile solvent. The portion of the formulation that remains followingat least partial evaporation can be referred to as the “nonvolatile” or“residual” phase, and the volatile element(s) of the formulation thatevaporate from the skin surface represents the “volatile” phase.

In certain embodiments, the pharmaceutical compositions may include aninert excipient that assists with increasing the concentration of thedetomidine or salt thereof in the residual phase following topicalapplication. In effect, such excipients can cause “salting out” of thedetomidine or salt thereof from the other components of the residualphase, which can have the effect of increasing the activity of thedetomidine or salt thereof on the surface of the subject's skin andpromote permeability of the drug through the skin. Such inert excipientscan include, for example, a polyol or simple sugar, such as sucrose,dextrose, trehalose, mannitol, sorbitol, or xylitol.

In certain embodiments, pharmaceutical compositions may comprise a foam.Foams according to the present disclosure may include a hydrophobicphase member that comprises, for example, a medium chain triglyceride,mineral oil, or both. The hydrophilic phase member in the foams mayinclude, for example, one or more of propylene glycol, hexylene glycol,1,3-propanediol, 1,2-pentanediol or water.

The pharmaceutical compositions may comprise a cream. In creamformulations, the hydrophobic phase member may comprise, for example,mineral oil, isopropyl isostearate, isostearyl isostearate, alkylbenzoate, butyl stearate, diisopropyl adipate, diethylhexyl adipate,caprilic/capric triglyceride, isocetyl stearate, isopropyl myristate,isopropyl palmitate, lauryl lactate, myristil myristate, ethylhexylcocoate, ethylhexyl palmiatate, ethylhexyl pelagronate, ethylhexylstearate, diethylhexyl succinate, propylene glycoldicaprylate/dicaprate, PPG-2 myristyl ether propionate, pentaerythrityltetracaprylate/caprate, pentaerythrityl tetra isostearate, isotridecylisononanoate, or any combination thereof. The hydrophilic phase membermay be, for example, glycerol, propylene glycol, water, 1,3-propanediol,1,2-pentanediol, hexylene glycol, butylene glycol, or any combinationthereof. Cream formulations may further comprise a fatty alcohol, anester of a fatty alcohol, or both, an emulsifier, an emollient, or anycombination thereof, including each of these components.

In accordance with the presently disclosed methods, the topicaladministration may be performed using conventional techniques. Forexample, the administration may be performed by delivering an aliquot ofthe pharmaceutical composition to a physician's or subject's hand, whichis used to smear and then rub the pharmaceutical composition onto anarea of skin on the body part for which treatment is desired. In thecase of a spray patch, the pharmaceutical composition may be sprayedusing any suitable mechanism, such as an aerosol, mister, spray bottle,or the like. The pharmaceutical composition may be topicallyadministered in the chosen manner on a once-daily, twice-daily orthree-times daily basis. When the method comprises applying thecomposition on a twice-daily basis, appropriate temporal spacing betweenapplications should be used. For example, if the subject is awake for a16 hour period of the day, then a first application can be performed inthe morning, and a second application can be performed in the evening,for example, prior to retiring to bed.

EXAMPLES

The following examples are set forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods, compositions, and components claimed herein are made andevaluated, and are intended to be purely exemplary of the invention andare not intended to limit the scope of what the inventors regard astheir invention.

Example 1: Topical Detomidine Gels

Topical formulations containing detomidine HCl were prepared. Theprepared formulations are described in Table 1.

TABLE 1 Formulation 0.01% 0.033% 0.10% 0.33% 1.00% Detomidine HCI 0.01% 0.03% 0.10% 0.33% 1.00% Hydroxyethyl cellulose (Natrosol 250 HH) 1.75% 1.75% 1.75% 1.75% 1.75% Glycerin 0.30%  0.30% 0.30% 0.33%    3%Propylene Glycol 0.10%  0.10% 0.10%    1%    1% Transcutol P 0.10% 0.10% Benzalkonium Chloride as 0.5% sol in water 0.02%  0.02% 0.02%0.02% 0.02% Ad 100% Tris buffer Buffer Buffer Buffer Buffer 0.05 MPhosphate Citrate Citrate Citrate pH 8.2 0.05 M 0.05 M 0.05 M 0.2 M pH7.2 pH 5.5 pH 5.5 pH 5.2

Example 2: In Vitro Binding Assay

Comparative radioligand binding assays of detomidine and clonidine wereperformed (Eurofins, Taiwan) using human recombinant cell lines. Theresults are shown in Table 2, with ≥50% inhibition demonstrating asignificant response. All results shown are at 10 μM, identifiedpreviously unknown binding affinities for detomidine for both H₄ andSST₄ receptors.

TABLE 2 % inhibition % inhibition Assay (detomidine) (clonidine)Adrenergic α1A 99 91 Adrenergic α1B 97 85 Adrenergic α1D 95 85Adrenergic α2A 97 94 Adrenergic α2B 104 101 Adrenergic α2C 100 97Histamine H4 68 2 SST4 35 13

Example 3: In Vitro Functional Assay

Cellular and nuclear receptor functional and enzyme uptake assays ofdetomidine and clonidine were performed (Eurofins, France). The highestconcentration tested was 10 μm and possible activity above thisconcentration was not determined in the assay. The results are shown inTable 3 and demonstrate that in addition to its known agonist activityfor alpha adrenergic receptors, detomidine also possesses agonisticproperties for both H₄ and SST₄ receptors. Both H₄ and SST₄ agonism havebeen identified as potential pathways for the topical treatment ofvarious types of pruritus.

TABLE 3 detomidine clonidine EC₅₀ EC₅₀ Adrenergic α1A agonist 1.9 nMagonist 3 nM Adrenergic α1B — not — not determined determined Adrenergicα1D — not — not determined determined Adrenergic α2A agonist 23.5 nMagonist 21.7 nM Adrenergic α2B agonist 36 nM agonist 30 μm Adrenergicα2C agonist 0.3 nM agonist 4.4 nM Histamine H4 agonist 4.7 μm not testedSST₄ agonist 7.3 μm not tested

Example 4: In Vitro β-Arrestin Assay

In order to determine whether detomidine functions as an H₄ agonist orinverse agonist, histamine (a known H₄ agonist), A 943931 (a known H₄antagonist) and detomidine were assayed using a GPCR internalizationassay which provided a quantitative measurement of arrestin-mediatedGPCR internalization of HRH₄ (Eurofins Discover X, USA). The results areshown in Table 4 and demonstrate that detomidine is an H₄ agonist.

TABLE 4 Compound Assay format Result type RC₅₀ /μM Histamine AgonistEC₅₀ 0.03 A 943931 Antagonist IC₅₀ 0.07 Detomidine Agonist EC₅₀ 9.6Antagonist IC₅₀ >100 Inverse agonist EC₅₀ >100

Example 5: Peripheral Neuritis Trauma (PNT)-Induced Neuropathic Pain inPigs

The analgesic effect of detomidine was assessed in a PNT-inducedneuropathic pain in pigs (MD Biosciences/Lahav Institute of Research,Israel). 30 pigs were anaesthetized and an incision of 8-10 cm madethrough the skin and fascia on the left side of their lower backs,approximately 1 cm lateral and parallel to the spine line. The muscleswere retracted and the sciatic nerve exposed. Following exposure, PNTwas induced by loosely tying (1-2 mm apart) around the lateral half ofthe sciatic nerve bundle, three 3-0 silk threads, each previouslyimmersed in complete Freund's adjuvant.

14 days after surgery and once chronic neuropathic pain had beenestablished, treatment was initiated according to the protocol shown inTable 5.

TABLE 5 No. Dose Dosing Dosing of Con- volume Route and TreatmentAnimals centration (ml) Regimen Placebo 6 N/A 4 mL Topical, twice dailyto Detomidine 0.1% 6  0.1% 4 mL the outer area of the Detomidine 0.33% 60.33% leg innervated by the Detomidine 1% 6    1% injured sciatic nerveGabapentin 6 6 mg/kg — IV, 1 hour prior to the (positive control) 1^(st)Von Frey test on Days 0, 1, 7 and 14

At time points over the following 14 days, the animals were assessed fora variety of pain and motor parameters. Stimulus-evoked pain wasassessed using Von Frey (VF) filaments and shown to demonstrate adose-dependent analgesic effect, with detomidine alleviating pain in,comparison to placebo, a statistically significant manner by increasingVF withdrawal threshold from Day 0 of treatment. Tactile stimulation,utilizing a 12-13 cm pigeon feather, showed that detomidine demonstrateda dose-dependent decreased tactile allodynia in response to light(non-painful) stimulus as soon as Day 0. Spontaneous pain behavior andGeneral Behavioral Score (GBS) was assessed by monitoring solitaryperformance and social behavior of each animals at 3 h and 6 h post-doseand showed that detomidine demonstrated a dose-dependent reduction inGBS scores from Day 0, indicative of decreased spontaneous pain inresponse to treatment. An open field motor test assessed motor functionand any potential sign of sedation and showed that detomidine did notaffect locomotor activity at any dose level throughout the study,indicating that topical administration of detomidine did not cause anysedative effect in the animals. The results of the stimulus-evoked painstudy are shown in FIG. 1. These results show topical detomidine effectsin significant pathologies associated with pruritus of neuropathicorigin.

Following completion of the study, skin biopsies were taken from theouter area of the leg of the placebo treated animals and immunostainedusing anti α2A adrenergic receptor polyclonal antibodies. Images weretaken of the stained tissue using ×20 objective, total magnification×200, scale bar 100 μm (Image a) or ×40 objective, total magnification×400, scale bar 50 μm. (Images b and c). The results of the staining areshown in FIG. 2 and show positive staining in epidermis (full thickness)(Epi), hair follicles (HF), blood vessels (BV) and nerves (N) for α2Aadrenergic receptors. These results identify the previously unknownpresence of α2adrenegric receptors in the skin and local surroundingtissues, potentially allowing for substantially non-systemic amounts ofdetomidine to be therapeutically effective when administered topically.

Example 6: Acute Itch Model

150 μl of vehicle or 0.10%, 0.33% or 1.00% topical formulations ofExample 1 were administered topically over a 2 cm² area of groups of 8mice (4 male, 4 female) for 5 consecutive days (Days 1-5). An activecontrol group of 8 additional mice were intraperitoneally administered asingle dose of U-50,488 (CAS 67198-13-4), a selective κ-opioid agoniston Day 5.

On Day 4, 2 mice (1 male, 1 female) in the 1.00% topical formulationgroup died, all other mice completed the treatment protocol. On Day 5,30 minutes after the administration of either vehicle, control ordetomidine, 0.4 mg of chloroquine was injected subcutaneously to themice. The number of scratching events were recorded for each of the 5groups at 5 minute intervals from the chloroquine administration over a30 minute total duration.

Each of the topical formulations of Example 1 were each found to reducethe number of scratching events in a statistically significant fashionover each 5 minute time point between time zero and 30 minutes. U-50,488was found to reduce the number of scratching events in a statisticallysignificant fashion over each 5 minute time point between time zero and15 minutes. Apart from the death of the 2 mice on Day 4, no otheradverse events were noted for any dose tested. A graphicalrepresentation of the number of scratching events over time is shown inFIG. 3.

Example 7: Clinical Efficacy of Topical Detomidine

In a double blind, vehicle controlled, randomized crossover designstudy, the safety and efficacy of topically applied 0.1 and 1 wt %detomidine hydrochloride is assessed for the treatment of pruritus.

The study consists of a Screening Period of up to 7 days during whichinclusion/exclusion criteria will be reviewed. Subjects meetinginclusion/exclusion criteria have a score of at least 5 on the 11-PointNumeric Rating Scale (NRS) for Pruritus will complete the one weekScreening Period. Subjects will complete a daily diary for NRS forPruritus scores and Sleep scores. At the end of the Screening Period,subjects who have a NRS for Pruritus score of at least 5 recorded in thediary on at least 4 of the 7 days preceding Day 0 will be eligible tocontinue. Baseline assessments will be recorded for vital signs,pruritic body surface area, skin integrity, PQOL, and laboratoryresults. The Baseline period will be followed by a 2 week TreatmentPeriod 1 in which subjects will be randomized to 0.1 wt % detomidinehydrochloride gel or Placebo gel to be applied QD for 14 days. Duringthe 2 week Treatment Period subjects will complete daily diaries of NRSfor Pruritis scores and Sleep scores. On Day 14 subjects will return tothe clinic to review diaries, adverse events (AEs), concomitantmedications, and to record body surface area for pruritus, skinintegrity, PQOL, and laboratory results. Subjects will then enter aWashout Period for up to 56 days until the subject again scores at least5 on the NRS for Pruritus on 4 consecutive or 4 of the past 7 days or 56days pass. Subjects will then enter a 2 week Treatment Period 2 duringwhich the same procedures as Treatment Period 1 will be performed exceptsubjects will receive the alternate treatment to that assigned inTreatment Period 1.

We claim:
 1. A method of treating pruritus as a symptom of aneurological condition in a subject in need thereof comprising topicallyadministering to the subject a pharmaceutical composition comprising0.01-5 wt % of detomidine.
 2. The method of claim 1, wherein thepruritus is acute.
 3. The method of claim 1, wherein the pruritus ischronic.
 4. The method of claim 1, wherein the neurological condition isnotalgia paresthetica, brachioradial pruritus, postherpetic neuralgia,stroke, small fiber neuropathy, trigeminal trophic syndrome,Creutzfeldt-Jakob disease, chemotherapy-induced neuropathy, HIV-relatedneuropathy or multiple sclerosis.
 5. The method of claim 1, wherein thedetomidine is detomidine hydrochloride.
 6. The method of claim 5,wherein the detomidine hydrochloride is anhydrous detomidinehydrochloride.
 7. The method of claim 5, wherein the detomidinehydrochloride is detomidine hydrochloride monohydrate.
 8. The methodclaim 1, wherein the pharmaceutical composition is in the form of a gel,a cream, an ointment, an emulsion, an emu-gel, a foam, a suspension or aspray-patch.
 9. The method of claim 8, wherein the pharmaceuticalcomposition is in the form of a gel.
 10. The method of claim 1, whereinthe pharmaceutical composition comprises 0.033 wt %, 0.1 wt %, 0.33 wt %or 1 wt % detomidine.
 11. The method of claim 1, wherein thepharmaceutical composition comprises detomidine as the sole activeagent.
 12. The method of claim 1, further comprising administering tothe subject at least one additional active agent.
 13. The method ofclaim 12, wherein the additional active agent is selected from the groupconsisting of corticosteroids, doxepine, tacrolimus, pimecrolimus,pramoxine, lidocaine, prilocaine, ketamine, amitriptyline, capsaicin,menthol, camphor, strontium, tofacitinib, crisaborole,N-palmitoylethanolamine, an antihistamine, an SNRI, an SSRI, naltrexone,butophanol, nalfurafine, gabapentin, pregabalin, aprepitant,thalidomide, lenalidomide, ursodeoxycholic acid, rifampin,cholestyramine, phenobarbital, Botulinum toxin A, naloxone, ASN008,SNA-125, TS-022, KPL-716 or orvepitant.
 14. The method of claim 12,wherein the additional active agent is administered topically.
 15. Themethod of claim 12, wherein the administration of the additional agentis administered orally or parenterally.
 16. The method of claim 1,wherein pharmaceutical composition is administered once daily.
 17. Themethod of claim 1, wherein the pharmaceutical composition isadministered twice daily.
 18. A method of treating pruritus as a symptomof a neurological condition in a subject in need thereof comprisingtopically administering to the subject a therapeutically effective,substantially non-systemic amount of detomidine.
 19. The method of claim18, wherein the detomidine is administered as a pharmaceuticalcomposition comprising 0.01-5 wt % detomidine.
 20. The method of claim19, wherein the pharmaceutical composition is in the form of a gel, acream, an ointment, an emulsion, an emu-gel, a foam, a suspension or aspray-patch.